Two protocols have been developed and approved (91-DK-133 and 91-DK-97) to use positron emission tomography (PET) and NMR spectroscopy to study insulin and IGF-I action in patients with insulin resistance. Both studies use the euglycemic glucose clamp with determination of glucose turnover using the isotope dilution method. PET and NMR are used to study regional hormonal effects in selected tissues such as muscle and fat. We have recently published a case report utilizing this methodology to gain new insights into IGF-II mediated hypoglycemia in a patient with hepatoma (J Clin Invest 89:1958-1963;1992). Seven patients (6 insulin resistant, 1 normal) have been entered in the study, and 5 have had euglycemic glucose clamps with insulin and IGF-I. The protocols are on hold by the FDA because a patient had bradycardia leading to asystole while receiving intravenous IGF-I. Using NMR spectroscopy it has been possible to isolate the signal from leg glycogen without enrichment with 13C-glucose. Studies with PET have not been done to date. One patient with severe insulin resistance and diabetes is receiving IGF-I treatment with benefit, and has been allowed to continue by the FDA.